The recognition of carbohydrates by lectins has been found to play an important role in various aspects of eukaryotic physiology. A number of different animal and plant lectin families exist, but it is the calcium dependent, or type C, lectins that have recently garnered the most attention. For example, the recognition of carbohydrate residues on either endothelial cells or leukocytes by the selectin family of calcium dependent lectins has been found to be of profound importance to the trafficking of leukocytes to inflammatory sites. Lasky, L., Ann. Rev. Biochem., 64 113-139 (1995). The biophysical analysis of these adhesive interactions has suggested that lectin-carbohydrate binding evolved in this case to allow for the adhesion between leukocytes and the endothelium under the high shear conditions of the vasculature. Alon et al., Nature (1995) in press. Thus, the rapid on rates of carbohydrate recognition by such lectins allows for a hasty acquisition of ligand, a necessity under the high shear of the vascular flow. The physiological use of type C lectins in this case is also supported by the relatively low affinities of these interactions, a requirement for the leukocyte rolling phenomenon that has been observed to occur at sites of acute inflammation. The crystal structures of the mannose binding protein (Weis et al., Science 254, 1608-1615 [1991]; Weis et al., Nature 360 127-134 [1992]) and E-selectin (Graves et al., Nature 367(6463), 532-538 [1994]), together with various mutagenesis analyses (Erbe et al., J. Cell. Biol. 119(1), 215-227 [1992]; Drickamer, Nature 360, 183-186 [1992]; Iobst et al., J. Biol. Chem. 169(22), 15505-15511 [1994]; Kogan et al., J. Biol. Chem. 270(23), 14047-14055 [1995]), is consistent with the supposition that the type C lectins are, in general, involved with the rapid recognition of clustered carbohydrates. Together, these data suggest that type C lectins perform a number of critical physiological phenomena through the rapid, relatively low affinity recognition of carbohydrates.
While a number of different type C lectin families are known, a particularly unusual group is that represented by the macrophage mannose (Taylor et al., J. Biol. Chem. 265(21), 12156-62 [1990]; Harris et al., Blood 80(9), 2363-73 [1992]), phospholipase A2 (Ishizaki et al., J. Biol. Chem. 269(8), 5897-904 [1994]; Lambeau et al., J. Biol. Chem. 269(3), 1575-8 [1994]; Higashino et al., Eur. J. Biochem. 225(1), 375-82 [1994]) and DEC 205 (Jiang et al., Nature 375(6527), 151-5 [1995]) receptors. While most of the members of the type C lectin group contain only a single carbohydrate binding domain, these three receptors contain either 8 (macrophage mannose and phospholipase A2 receptors) or 10 (DEC 205 receptor) lectin domains, and it is likely that these domains cooperate with each other to enhance ligand avidity (Taylor et al., J. Biol. Chem. 267(3), 1719-20 [1992]; Taylor et al., J. Biol. Chem. 268(1), 399-404 [1993]). All three of these molecules appear to be type 1 transmembrane proteins, and they all appear to mediate various endocytic phenomena. Accordingly, this family will hereafter be referred to as the endocytic type C lectin family (Harris et al, supra; Jiang et al., supra; Zvaritch et al., J. Biol. Chem. 271(1), 250-7 [1996]). The endocytic mechanism is particularly important in the case of the macrophage mannose receptor, expressed predominately on macrophages and liver endothelium (Harris et al., supra), and the DEC 205 receptor (Jiang et al. supra), expressed specifically on dendritic and thymic epithelial cells. Thus, both of these receptors appear to mediate the endocytosis of large particulate (ie. pathogens such as yeast) (the macrophage mannose receptor) or highly glycosylated molecular (the DEC 205 receptor) complexes. In both cases, the endocytosis of glycosylated complexes by these receptors is involved with the transport of either particles or glycoproteins to the endosomal pathway where they are degraded and, in the case of the DEC 205 receptor, efficiently presented to cells of the immune system by the dendritic or thymic epithelial cells (Jiang et al, supra). It therefore seems likely that both of these receptors are involved with the presentation of highly glycosylated structures to immune cells to allow for efficient responses against pathogenic organisms. Interestingly, the phospholipase A2 receptor is also likely to be involved with the endocytic uptake of extracellular proteins, although in this case it appears to be an endogenous protein, ie. one or more phospholipases (Ishizaki et al., supra; Lambeau et al., supra; Higashino et al., supra; Zvaritch et al., supra). The exact biological function of this receptor, other than as a high affinity mediator of phospholipase binding, is unknown, and its tissue expression pattern appears to be far broader than that of the other two receptors in this family (Higishino et al., supra). In addition, it is not clear that the binding of phospholipase to this receptor is mediated by protein-carbohydrate interactions, although this receptor is clearly capable of binding glycosylated proteins (Lambeau et al., supra). In summary, all three of the known members of this family of type C lectins appear to be involved with the binding and uptake of either large particulate or molecular complexes into the endocytic pathway of the cell, and in the case of both the macrophage mannose and DEC 205 receptors, these interactions appear to be via protein-carbohydrate recognition.